There are several forms of kidney cancer. The most common form is referred to as clear cell renal carcinoma. The initiating event in most clear cell renal carcinomas is the inactivation of a protein called the VHL tumor suppressor protein. Loss of the VHL protein leads to increased activity of several proteins that belong to the HIF protein family. We showed before that increased activity of one of the HIFs, called HIF2, promotes the growth of clear cell renal carcinomas. HIF2 is a so-called transcription factor and controls the activity of over 100 genes in clear cell renal carcinomas, including the gene that governs the production of vascular endothelial growth factor (VEGF). It has been well established that drugs that block VEGF are helpful for treating clear cell renal carcinomas but they are not curative. We believe that targeting HIF2 itself will be far more effective than simply blocking one of the many genes it activates (such as VEGF). We are working closely with Peloton Therapeutics, which has developed a drug that blocks HIF2 function in laboratory models. In aim 1 and 2 we will conduct a clinical trial to determine if this drug can, indeed, block HIF2 activity in man and, if so, whether this leads to clinical benefit for patients with clear cell renal carcinoma. In aim 2 we will also develop new ways of monitoring HIF2 activity in clinical samples. In aim 3 we will ask whether blocking HIF2 function can, as expected, enhance the antitumor effects of VEGF inhibitors against clear cell renal carcinomas in mouse models of this disease. We recently made the unanticipated discovery that thalidomide, which has become an important drug for the treatment of a cancer called multiple myeloma, works by earmarking two transcription factors (called IKZF1 and IKZF3) for destruction. This gives us hope that we could, in time, discover drugs that likewise mark the HIF2 transcription factor for destruction. We will attempt to identify such drugs in aim 4. If successful, such drugs should markedly enhance the actions of drugs, such as the Peloton drug, that block HIF2 function. In addition, combining two drugs that inhibit HIF2 in two different ways should decrease the emergence of clear cell renal carcinoma cells that are resistant to therapy (since they would now have to circumvent two forms of attack on the same target).